Efficacy and Safety of Memantine Treatment for Reduction of Changes Associated with Experimental Glaucoma in Monkey, I: Functional Measures

Hare, William A.; WoldeMussie, Elizabeth; Lai, Ronald; Ton, Hau; Ruíz, Guadalupe; Chun, Teresa; Wheeler, Larry A.

doi:10.1167/iovs.03-0566

Cited by 135 publications

(83 citation statements)

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“…Vertical sections from the central calotte that crossed near the foveal depression, and from the temporal and nasal calottes, were used for morphometry using methods and strategy as in previous work (e.g., La Vail et al, 2000;Hare et al, 2004;Leung et al, 2005). Contiguous fields, extending from the central retina into the far superior and inferior retina, were imaged at ϫ10 magnification with a camera (Olympus BH2; Olympus America, Melville, NY) attached to a microscope (Leica DFC480; Leica Microsystems, Bannockburn, IL).…”

Section: Necropsy and Histopathologymentioning

confidence: 99%

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

et al. 2006

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Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2. RPE65 in RPE65 -mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vectorrelated toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2. RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2. RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina. KeywordsLeber congenital amaurosis, blindness, mutated dogs, retina, injection, dogs and safety data with rAAV-2/2.RPE65. Questions about systemic and retinal toxicity are asked in a nonhuman primate, the only mammal with a foveate retina like that of humans, to determine whether there is sufficient safety to initiate human clinical trials.

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Section: Necropsy and Histopathologymentioning

confidence: 99%

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

et al. 2006

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“…Memantine, an inhibitor of glutamate flux through the N-methyl-D-aspartate receptor, is clinically used in neu rological disorders, such as Alzheimer's dementia. (99,100) Although several preclinical studies have demonstrated that memantine had a neuroprotective effect (101)(102)(103) , a large randomized clinical trial failed to show the same effect in human glaucoma (data not published) (104) . The Memantine Trial actually showed that the progression of disease was significantly lower in patients receiving the higher dose of memantine than those receiving the low dose.…”

Section: Treatmentmentioning

confidence: 99%

Normal-tension glaucoma: an update

Esporcatte¹,

Tavares²

2016

Arquivos Brasileiros De Oftalmologia

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However, several structural and functional differences support the fact that different mechanisms may have a stronger role in the pathogenesis of NTG versus high-pressure POAG. Also, a recent study reported genetic variants associated with different tendencies towards POAG with lower or higher IOP (6) . Furthermore, clinical impression and anecdotal evidence suggest that NTG with mean IOP in the high teens (>15 mmHg), in which circadian fluctuation and CCT could lead to a possible misdiagnosis of an IOP ≤21 mmHg, would differ from NTG with mean IOP in the low teens (≤15 mmHg), with different ABSTRACT Descritores: Glaucoma de ângulo aberto; Pressão in traocular; Doenças do nervo óptico; Anti-hipertensivos/uso terapêuticopathogenesis and progression patterns, harder to achieve target IOP, and higher incidence of disc hemorrhages. Nonetheless, a recent report does not support this assumption and underscores low-teens NTG as an important entity (7) . The proportion of NTG varies depending on different population studies. In Asian epidemiological protocols, NTG constituted the majority of open-angle glaucomas (52%-92%), depending on the country and study methodology (8) . Normal IOP was measured in 57.1% cases of POAG in a South African study (9) . In white populations, the proportion of NTG was lower than that observed in Asian and African populations. In studies conducted in the United States, Netherlands, and Italy, NTG presented proportions of 31. 7%, 38.9%, and 30%, respectively (10-12) . The etiology of NTG is most likely multifactorial and still not well defined. Moreover, several alternative treatments based on this different pathogenesis have been discussed. The objective of this study was to review the mechanisms involved in the onset and progression of NTG and the efficacy of established and alternative therapies for NTG treatment. PathogenesisThe pathogenesis of NTG is unclear, and perhaps the development of the disease is a consequence of a complex interaction of several systemic and ocular factors. Different studies have shown that the cardiovascular system and intracranial pressure may be involved in the main pathways of optic nerve damage. Nevertheless, the complex relationship between these mechanisms and glaucoma pro gression continues to be debated.

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“…12 In a study of chronic ocular hypertension in the primate, histological measurements showed that, for animals with moderate elevation of IOP, oral administration of memantine was associated with an enhanced survival of RGCs in the inferior retina. 13,14 Measurements of optic nerve head topography with confocal scanning laser tomography (HRT) showed less IOP-induced change in animals treated with memantine, as reflected in measurements of the cup and neuroretinal rim (Figure 3). In addition, the findings indicate that memantine treatment is safe.…”

Section: 6mentioning

confidence: 99%

“…When responses from animals with severe RGC loss were compared, vehicle-treated animals had lost most of the VEP response while responses obtained from memantinetreated animals were of relatively normal amplitude. 13 Further research has focused on whether memantine increases neuronal functionality, in some way, in addition to its neuroprotective effects. A neurological study showed that memantine increases brain metabolism and effectively treats mild-to-moderate Alzheimer's disease.…”

Section: 6mentioning

confidence: 99%

Neuroprotection: new pharmacological targets

Wheeler

Lai

WoldeMussie

et al. 2007

Eye

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Recent research in the field of neuroprotection in glaucoma has focused on the N-methyl-D-aspartate (NMDA) and the a-2 adrenergic receptor systems. Experimental findings have shown that brimonidine (BMD), a specific a-2 adrenoceptor agonist, can protect against loss in mitochondrial membrane potential during oxidative stress, and preserve anterograde axonal transport. Memantine is a selective blocker of the NMDA-type glutamatergic type ion channel. It has unique open channel blocker properties that result in a preferential inhibition of excessive (excitotoxic) neuronal activation by high levels of glutamate without interfering with the channel's normal functions. In a primate model, memantine was neuroprotective as can be seen from its effect on maintaining/ preserving RGCs. Research in Alzheimer's disease has demonstrated that memantine may increase neuronal functionality as well as being protective. Research in a primate glaucoma model shows that memantine protects neurons from shrinking in the lateral geniculate nucleus. Memantine is currently in clinical trials for glaucoma.

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Efficacy and Safety of Memantine Treatment for Reduction of Changes Associated with Experimental Glaucoma in Monkey, I: Functional Measures

Abstract: Systemic treatment with memantine, a compound which does not lower intraocular pressure, was both safe and effective for reduction of functional loss associated with experimental glaucoma.

Cited by 135 publications

References 0 publications

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

Normal-tension glaucoma: an update

Neuroprotection: new pharmacological targets

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